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Therapeutics

New visions in ophthalmic drug development

Over the last 10 years we have seen the introduction of several new ‘ only’ pharmaceutical products emerge such as Trusopt (dorzolamide, Merck) and Xalatan (latanoprost, Pharmacia). Innovative products such as these have driven much of the ophthalmic pharmaceutical growth, outpacing the older products that were often developed for ophthalmology via other therapeutic areas.With the ophthalmic pharmaceutical sector currently at around $5 billion worldwide, the continued growth is likely to be driven by even more first-in-class entries in ophthalmology.Two areas that are especially poised for explosive growth are dry and retinal disease, in which many new therapeutic approaches are currently in development.

ecent changes and restructuring in corpo- ing of EyeTech, which raised $100 million for a By Dr Benjamin R. rate aspects of the ophthalmology market- ‘biotech’ anti-angiogenesis project for treating reti- Yerxa, Dr Ward M. R place will likely influence the future of nal disease in August 2001. Other biotechnology Peterson and Robin ophthalmic drug discovery. For example, in 1999 and pharmaceutical companies, such as S.Whitsell Bausch and Lomb, a company with few propri- Genentech, Inspire, ISTA and Eli Lilly have invest- etary prescription products, restructured itself by ed significant cash and resources into their selling its Miracle Ear hearing aid, Charles River advanced stage ophthalmic products. Shifts like and Ray Ban divisions. It then essentially used the these in ophthalmic pharmaceutical R&D are proceeds to purchase the European-based eye care shaping the future of eye care. company Groupe Chauvin for $228 million in cash. This movement helped to reposition Bausch Emerging areas and Lomb for growing its global prescription drug Several disease areas of ophthalmology are under- business. In July 2002 Allergan spun out its optical served by prescription pharmaceuticals. The medical device business to create Advanced largest unmet medical needs are dry Medical Optics, transforming Allergan into a spe- and a number of retinal diseases, such as age-relat- cialty pharmaceutical ‘pure play’. On March 21, ed , diabetic and 2002 Nestle spun out Alcon in an IPO valued at pigmentosa. These conditions have been about $2.3 billion, creating the world’s largest under-served primarily because of their complex independent eye care company. Other transactions etiology and progression, which has eluded the have raised attention, such as the start-up financ- development of new drugs. In recent years, insight

Drug Discovery World Winter 2002/3 51 Therapeutics

Figure 1 Cross-section of the eye highlighting ocular surface Main lacrimal structures.The eye seen in gland cross-section reveals the main and accessory lacrimal glands that secrete bulk fluid and proteins, and the meibomian glands in the that Accessory produce lipids.The conjunctival lacrimal glands surface joins with the and surrounds the inner eye lids, producing mucus and additional fluid to directly hydrate the ocular surface

Cornea

Meibomian glands

into disease mechanisms and identifiable drug tar- effecting as many as 12 million people in the US gets has resulted in the emergence and develop- alone1. Despite the numerous over-the-counter ment of a number of promising drug candidates artificial available as tear substitutes, these that are now in late-stage clinical studies, particu- aqueous lubricant solutions provide short-lived larly for the treatment of dry eye disease, age-relat- relief of symptoms, but do not address the under- ed macular degeneration and . lying problems associated with the disease, nor do they have significant effects on ocular surface Dry eye health. Currently there are no approved, pharma- is a multifaceted disease charac- cologically active drugs for treating dry eye disease; terised by symptoms of chronic irritation and however, recent approaches to treating dry eye dis- inflammation (itching, burning, pain and gritty ease in clinical development include targeting sensations) and ocular surface damage (as evi- inflammation, secretion and hormones. denced by corneal and conjunctival staining)4. The health and integrity of the ocular surface are main- Anti-inflammatory tained by the fluid and protein secreting main and A major component of dry eye disease is the per- accessory lacrimal glands, the lipid producing mei- sistent ocular surface inflammation that occurs, bomian glands and the fluid and mucin secreting either primarily due to autoimmune diseases such conjunctival (Figure 1). as Sjögren’s syndrome, or secondarily as a result of Epidemiological studies of dry eye show an chronic dryness and irritation. Regardless of the increased prevalence in post-menopausal women, cause, inflammatory infiltrates release cytokines

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that accumulate on the ocular surface and slowly ued for only several days or a few weeks at a time. degrade and remodel the epithelium, leading to the In Sjögren’s disease patients, non-preserved corti- hallmark sign of dry eye: a compromised ocular costeroid treatment resulted in a desired decrease surface that can be assessed by corneal and con- of corneal staining and a resolution of filamentary junctival staining techniques. Anti-inflammatory . Some patients also experienced relief interventions have shown some promising results. from the symptom of irritation3. Restasis (cyclosporine A, Allergan), a topical immunosuppressant that reduces ocular surface Secretagogues inflammation, is currently undergoing a Phase 3 Since dry eye is a disease of impaired ocular surface clinical trial to confirm positive results from previ- hydration as measured by a marked decrease in tear ous Phase 3 trials2. Allergan received an approv- secretion particularly from the lacrimal glands, it is able letter from the FDA on August 24, 1999 and reasonable to expect that a pro-secretory approach expects to launch Restasis in late 2003. In would be beneficial. Despite the obviousness of November 2002, Debiopharm announced that a such an approach, secretagogue-based therapeutic more water-soluble prodrug of cyclosporine A may development for dry eye has not been successful. be developed as a treatment for dry eye. Another For example, muscarinic secretagogues (M3 recep- anti-inflammatory drug that is used systemically tor agonists) approved for dry mouth, such as for similar indications as cyclosporine, called FK- Salagen4 (, MGI) and Evoxac5 (cevime- 506 (, Fujisawa), is being developed out- line, Daiichi), have not been proven efficacious in side Asia for dry eye disease by Sucampo treating dry eye. This may be due in part to the mul- Pharmaceuticals. Tacrolimus for treating dry eye tiple components of ocular surface secretion, ie it is disease is currently in Phase 2 in Europe with plans a combination of glandular and epithelial secretion for future US studies in the coming years. that is under both neural regulation and nonadren- Topical , although generally con- ergic, noncholinergic control. traindicated for chronic use due to the risk of The most advanced secretagogue in clinical increases in IOP and formation, have been development is INS365 Ophthalmic Solution used as ‘pulse therapy’ in which dosing is contin- (diquafosol, Inspire), a P2Y2 nucleotide receptor

Ta b le 1: Dry eye in development

COMPANY COMPOUND TYPE OF PRESUMED PHASE OF DEVELOPMENT

Alcon 15-HETE Secretagogue Phase 2

Allergan Restasis Anti-inflammatory Phase 3

Allergan Androgen Tear Hormone Phase 3

Inspire INS365 Secretagogue Phase 3

Otsuka OPC-12759 Secretagogue Phase 2

Sucampo FK-506 Anti-inflammatory Phase 2

Drug Discovery World Winter 2002/3 53 Therapeutics

Ta b le 2:Wet AMD medications in development

COMPANY COMPOUND MEDICATION PRESUMED TYPE PHASE OF DEVELOPMENT

Alcon Anecortave Acetate subtenons Phase 3 injection

EyeTech Macugen Anti-angiogenesis Phase 3

Genaera Squalamine Anti-angiogenesis Phase 1

Genentech RhuFab Anti-VEGF intravitreal Entering Phase 3 injection

Miravent SnET2 PDT Post-Phase 3

Oxigene Combretastatin Vascular targeting agent Entering Phase 1/2

Novartis, QLT Visudyne PDT Approved

agonist. This nucleotide stimulates primarily con- in Phase 2 in the US, although results of patient tri- junctival epithelial secretion of salt, fluid and als have not been reported yet. mucin and possibly lipid secretion from the meibo- mian gland, thereby making up the principal layers Hormone replacement of the tear film. The conjunctival secretion can be Since dry eye is most common in post-menopausal stimulated with INS365 to provide normal tear women, the link to hormonal changes has been volumes even in animals in which the lacrimal studied extensively. Hormone replacement therapy glands have been removed6. INS365 is currently in by itself, however, has not been correlated with Phase 3 clinical testing in the US, although the decreased dry eye. In fact, the opposite appears to company recently reported that the FDA would be true9. Despite the epidemiological puzzle, consider an NDA filing based on the completed researchers at the Aborn Eye Research Center in studies to date. Inspire expects to launch INS365 in New York, are currently investigating a propri- the US in early 2004 with its partner Allergan. etary topical estradiol eye drop and have obtained Several mucin secretagogues are being developed positive, preliminary results from a small, single- for dry eye therapy. OPC-12759 (Rebamipide, centre, placebo-controlled Phase 2 trial in patients Otsuka), a gastric protectant approved in Japan, is with dry eye10. currently in Phase 2 in the US and is reported to Decreases in androgen hormone levels are also work via upregulation of mucin secretion and/or observed in post-menopausal women and in proliferation of mucin-containing goblet cells7. 15- Sjögren’s syndrome and are correlated with HETE, an intermediate in the arachidonic acid cas- decreased glandular secretion. It has been postu- cade, is being developed by Alcon as a dry eye lated that this hormone imbalance is responsible treatment and is reported to work via direct stimu- for drying of mucosal surfaces throughout the lation of mucin secretion8. 15-HETE appears to be body as women age. For the eye, a decrease in

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androgens may lead to dysfunction of the oil pro- optometrist during a routine eye examination. ducing meibomian glands in the eyelids (Figure 1). AMD is classified as dry or wet, depending on Since the outermost oily layer is responsible for whether there is fluid exudation arising from leak- providing tear film stability and preventing evapo- ing and proliferating choroidal blood vessels. rative loss of water, abnormalities in meibomian Although 90% of patients with AMD present with gland function lead to ‘evaporative’ forms of dry the dry form, actual blindness associated with eye11. The relationship between this as it relates to AMD is predominantly due to the wet form. dry eye disease is being studied in dry eye patients Nearly 200,000 people are blinded by AMD each (Androgen Tear, Allergan). Interestingly, a topical year, and because of the increasing elderly popula- androgen gel is being developed for vaginal dry- tion, it is estimated that there may be up to ness associated with menopause, and positive 500,000 new cases of blindness yearly in the US by results from patient trials have been reported the year 2030 given the current standard of thera- (Tostrell, Cellegy). py. There are essentially three modes of treatment developed or in development for treatment of wet Diseases of the AMD: photodynamic therapy (PDT), steroid ther- Corneal diseases, although debilitating, are not apy and anti-VEGF therapy. All other medications the leading causes of blindness. Conditions affect- in development are outside of these models. ing the retina, including classically inherited ones and those secondary to systemic diseases, are the Photodynamic therapy (PDT) culprits in the industrialised world. Primary The theory behind photodynamic therapy is to cre- among these diseases, according to a March 20, ate scarring at the precise area of neovascularisa- 2002 NEI press release, more than 5.3 million tion (the inappropriate leakage and proliferation of Americans are affected by diabetic retinopathy, blood vessels). The patient is given a drug that is which predominantly affects central vision. An intended to make blood vessels and specifically additional 1.6 million Americans over 60 years of neovascular areas photosensitive. Upon applying age have age-related macular degeneration, anoth- light via laser to those now sensitised areas, the er disease that destroys central vision12. In addi- underlying tissue will be destroyed effectively cau- tion, approximately 1 in 4,000 worldwide is terising the leakage. The only approved drug for afflicted with perhaps the most debilitating of all the treatment of wet AMD is based on this princi- inherited blinding diseases, . ple. Visudyne (Verteporfin, Novartis/QLT) was Hence, retinal diseases such as age-related macu- approved in the US in April 2000 for a minor sub- lar degeneration (AMD), diabetic retinopathy set of wet AMD. It is administered intravenously in (DR) and retinitis pigmentosa (RP) represent by its inactive form, where it is thought to accumulate far the largest areas of unmet medical needs and very specifically in choroidal neovascular cells. untapped pharmaceutical markets in ophthalmol- Following intravenous administration, a low-ener- ogy in industrialised nations. gy laser is used to activate the drug, which leads to Recent advances in the understanding of the the subsequent closure of the leaky blood vessels. underlying pathophysiology of AMD, DR and RP Patients treated with Visudyne require treatment have paved the way for the development of poten- up to four times a year. PhotoPoint SnET2 tial new drugs for halting or slowing the progres- (Miravent) is another PDT treatment under clinical sion of vision loss associated with these diseases. investigation. Analysis of two completed pivotal Although wet AMD and DR are very different dis- Phase 3 clinical trials for in January 2002 showed eases with unrelated etiology, there has been an that the drug did not achieve statistical significance emerging appreciation that similar vascular abnor- in primary efficacy endpoint. However, the Phase 3 malities (namely leakage and proliferation of results for PhotoPoint SnET2 are currently being choroidal blood vessels in wet AMD and leakage evaluated for efficacy in smaller subset populations and proliferation of retinal blood vessels in diabet- of AMD patients. ic retinopathy) play key roles in the symptomatic progression of both diseases. Anti-angiogenesis: anti-VEGF There is now very strong evidence that vascular Age-related macular degeneration endothelial growth factor (VEGF) protein plays a AMD is the leading cause of blindness in people predominant role in the progression of wet AMD over 60 years of age in industrialised nations13. and diabetic retinopathy. VEGF is a secreted sig- Most patients have non-symptomatic AMD, which nalling protein that is required for normal devel- can usually be diagnosed by an ophthalmologist or opment of the vasculature in the body. However,

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Figure 2 Cross-section of the eye highlighting posterior structures.A rhegmatogenous Retinal tear Fluid bleb is pictured in the upper hemisphere, Vitreous flow where a single retinal tear results in the accumulation of Detached retina vitreal fluid between the retina and retinal pigment epithelium. Other notable structures include the choroidal blood vessels and retinal blood Retinal pigment vessels. Proliferation and epithelium leakage of choroidal blood vessels behind the macula results in ‘wet’ AMD. Leakage and proliferation of retinal blood vessels result in diabetic retinopathy

Choroidal blood vessels

Retinal blood vessels

VEGF stimulation and signalling in diabetic Anti-angiogenesis: other approaches retinopathy and wet AMD causes otherwise stable Another new anti-angiogenic treatment under and mature endothelial cells to become leaky and development for wet AMD is an angiostatic proliferate in a process generally referred to as steroid, Anecortave Acetate (Alcon)16. Anecortave pathological angiogenesis. Pathological angiogene- Acetate has been shown in Phase 2 studies to be sis is also seen in the development of many types of effective in preserving vision and is currently in tumours, which secrete VEGF to stimulate the Phase 3 studies. Anecortave Acetate is given bi- local growth of new blood vessels to nourish the annually as sub-tenon injections near the exterior tumour. Putative anti-angiogenic therapies (partic- part of the back of the eye. This administration ularly anti-VEGF approaches) in development for route and the frequency of dosing are less invasive tumour regression are thought to be applicable for and much less frequent than the intravitreal injec- potentially treating angiogenic diseases of the reti- tion regimens that are required for delivery of na (and vice-versa). Multiple approaches that dis- Macugen and rhuFab V2. A less selective, corticos- rupt VEGF signalling are currently in clinical or teroid approach, in which a sustained release pellet late-stage preclinical ophthalmic drug develop- containing dexamethasone is implanted inside the ment. The most advanced of these compounds in eye, is being investigated for the treatment of dia- clinical development for wet AMD is the aptamer betic and is currently in Phase 2 tri- Macugen (Pegaptanib sodium, Eyetech)14, which als (Posurdex, Oculex). has completed enrollment in two pivotal Phase 3 The aminosterol squalamine (Genaera) is anoth- trials as of August 2002. An additional anti-VEGF er anti-angiogenic compound that inhibits VEGF- monoclonal antibody for wet AMD completed a induced, as well as other growth factor-mediated, Phase 1b/2 study in September 2002, rhuFab V2 endothelial cell activation, proliferation and migra- (Ranibizumab, Genentech)15. Phase 3 enrollment tion. Systemic administration of squalamine was for rhuFab V2 will reportedly begin in 2003. shown to be effective in inhibiting ocular neovas-

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cularisation in various preclinical models. Genaera kinase Cß (PKCß). Thus inhibition of PKCß may References initiated a Phase 1/2 study in August 2002 for offer a novel approach for treating - 1 Moss, S, Klein, R, Klein, BE. evaluating squalamine in patients with wet AMD. induced microvascular complications, including Prevalence of and risk factors for dry eye syndrome.Arch. Combretatstatin (CA4P, Oxigene), a novel anti- DR and peripheral neuropathy. An oral medication Ophth. 118 (9, p1264) 2000. angiogenic compound that specifically destabilises based on this approach, LY-333531 (Eli Lilly), is in 2 Sall, K, Stevenson, O, Mundorf, microtubules of newly formed endothelial cells, is late stage clinical development for the treatment of T, Reis, B.Two multicenter, also expected to enter into a Phase 1/2 study in DME and PDR. It is anticipated that filing for reg- randomized studies of the patients with wet AMD in the near future. ulatory approval of LY-333531 for diabetic efficacy and safety of cyclosporine ophthalmic retinopathy in Europe will occur in 2003. Also, a emulsion in moderate to severe P2Y2 receptor agonist somatostatin analogue, Sandostatin (octreotride, dry eye disease. CsA Phase 3 Since pathological accumulation of intra-retinal or Novartis), has been shown in multiple clinical stud- Study Group. Ophthalmology. sub-retinal fluid is a common feature and cause of ies to provide various patient benefit outcomes in 107 (4, p631-9) 2000. visual loss in diabetic retinopathy, wet AMD and DR. The underlying mechanism of action is not 3 Marsh, P,Pflugfelder, SC. Topical nonpreserved in a variety of other retinal diseases, such as cys- fully understood, but may involve vascular anti- methylprednisolone therapy toid macular edema, retinitis pigmentosa, central permeability and anti-proliferative effects owing to for keratoconjuntivitis sicca in serous retinopathy and retinal detachment, it is inhibition of growth hormone activity. Sjögren’s syndrome. thought that directly removing this fluid build-up An additional in PDR is vitreous Ophthalmology. 106 (4, p811- may offer therapeutic benefit. Stimulation of fluid haemorrhaging, which is a major cause of visual 6) 1999. 4Vivino, F,Al-Hashimi, I, Khan, transport across the retinal pigment epithelium, a loss for the patient. Vitrase (hyaluronidase, ISTA) Z, LeVeque, F,Salisbury, P,Tran- layer of cells juxtapositioned between the retina has completed Phase 3 studies for evaluating the Johnson,T, Muscoplat, C,Trivedi, and the choroidal blood supply, has been demon- efficacy in the resolution of vitreous haemorrhage. M, Goldlust, B, Gallagher, S. strated in animals by activating the P2Y2 recep- Although primary efficacy was not reached in the Pilocarpine tablets for the tors. This is expected to remove fluid from intra- Phase 3 studies, secondary analysis demonstrated treatment of dry mouth and dry eye symptoms in patients retinal and subretinal spaces (Figure 2). A P2Y2 improvement in visual outcomes following treat- with Sjögren’s syndrome: a receptor agonist (INS37217 Intravitreal Injection, ment and currently NDA approval is being sought. randomized, placebo-controlled, Inspire) is currently in clinical development using fixed-dose, multicenter trial. this novel approach for removing fluid build-up. A Retinitis pigmentosa P92-01 Study Group.Arch. Int. Phase 1/2 study was recently completed for Retinitis pigmentosa (RP) is the most common Med. 159 (2, p174-81) 1999. 5 Fox, R. Sjögren’s syndrome: INS37217, given as a single intravitreal injection, class of inherited photoreceptor degenerative dis- current therapies remain to patients with rhegmatogenous retinal detach- eases and affects approximately 1:4,000 world- inadequate for a common ments and enrollment in a Phase 2 study is expect- wide. An estimated 100,000 to 200,000 Americans disease. Expert Opin.Investig. ed to begin in 2003. have RP, which is a genetically heterogeneous dis- Drugs. 9 (9, p2007-16) 2000. ease generally characterised by similar phenotypic 6 Fujihara,T, Murakami,T, Fujita, H, Nakamura, M, Nakata, Diabetic retinopathy manifestations: loss of peripheral vision followed K. Improvement of corneal Diabetic , such as diabetic macular by loss of central vision. Some RP patients suffer barrier function by the P2Y2 edema (DME) and proliferative diabetic retinopa- complete blindness. No drugs are specifically agonist INS365 in a rat dry thy (PDR), are the leading cause of blindness in approved for RP. On-going approaches in develop- eye model. Invest Ophthalmol Americans under 60 years of age. Diabetic ment for inducing retinal neuroprotection (see Vis Sci. 42 (1, p96-100) 2001. 7 Fujihara, S, Urashima, K, retinopathy accounts for an estimated 12% of new below) may lead to new developments in RP, as Watanabe, K. Effect of OPC- cases of blindness each year. There are an estimat- may various gene or protein-based approaches cur- 12759 eye drops on the ed 65,000 new cases of PDR and 75,000 new cases rently in preclinical development. These include: amount of mucin-like of DME annually in the US alone. The current ribozyme gene therapy, cell-based delivery of cil- substances on the conjunctiva. standard treatment for PDR is laser photocoagula- iary neurotrophic factor (NT-501, Neurotech) and IOVS. 40 (4, S536) 1999. 8 Gamache, D,Wei, Z,Weimer, tion, causing micro-burns on the retina that effec- gene-based delivery of pigment epithelium-derived L, Miller, S, Spellman, J,Yanni, J. tively cauterise the bleeding vessels but also inacti- factor (PEDF). PEDF has been shown to promote Corneal protection by the vate the photoreceptors in that area. No medica- photoreceptor survival and inhibit ocular angio- ocular mucin secretagogue tion is currently approved for DR. genesis, and is currently being tested in Phase 1 15(S)-HETE in a rabbit model Many of the same compounds that are being (AdPEDF, GenVec) in AMD patients. of desiccation-induced corneal defect. J Ocul Pharmacol Ther. developed for wet AMD are also being studied in 18 (4, p349-61) 2002. PDR, notably Visudyne. In addition, anti-angiogen- Neuroprotection 9 Schaumberg, D, Buring, J, esis compounds are also being explored. A number Therapeutic approaches that confer direct neuro- Sullivan, D, Dana, M. Hormone of studies have shown that the immediate down- protection of retinal neurons remain perhaps the replacement therapy and dry stream effects of VEGF signalling in microvascular most elusive to develop. If effective at prolonging eye syndrome. JAMA. 286 (17, p2114-9) 2001. endothelial cells, including those of the retinal vas- survival and function of retinal ganglion cells and culature, is predominantly mediated by protein photoreceptors, a neuroprotective drug may be Continued on page 59

Drug Discovery World Winter 2002/3 57 Therapeutics

used to treat diseases such as , wet and Scientist in the chemistry department at Burroughs Continued from page 57 dry AMD, retinitis pigmentosa, cone-rod dystro- Wellcome. Dr Yerxa received his PhD in Organic 10 Lubkin,V.Topical estradiol phy and a variety of photoreceptor-specific degen- Chemistry from UC Irvine in 1993. effectively treats post- erations. An oral NMDA receptor antagonist menopausal dry eye, study (memantine, Allergan) is in Phase 3 clinical testing Ward M. Peterson, PhD received his PhD in shows apatented application of for glaucoma/neuroprotection. Memantine is Biophysics from the Department of Molecular and this hormone showed promise already approved in Europe for the treatment of Cell Biology and Department of at the in a phase 2 study.A phase 3 17 multicenter trial is about to moderately severe to severe Alzheimer’s disease . University of California, Berkeley in 1995. begin. Ocular Surgery News. There has also been a great deal of animal research Currently Senior Director of Preclinical Programs 19 (23, p34) 2001. around alpha-2 adrenergic agonists as potential at Inspire, he is also the project leader for 11 Sullivan, D, Sullivan, B, Evans, J, neuroprotective agents and it is speculated that INS37217 Ophthalmic. He received a National Schirra, F,Yamagami,H, Lui, M, Alphagan (brimonidine, Allergan) is in Phase 2 Research Service Award and a Foundation Fighting Richards, S, Suzuki,T,Schaumberg, D, Sullivan, R, Dana, R.Androgen clinical trials for this application. Blindness fellowship for post-doctoral studies con- deficiency, ducted at UC San Francisco and Berkeley and dysfunction, and evaporative dry Conclusions University of Florida. Prior to joining Inspire in eye. NY Acad Sci. Jun (966, p211- It is evident that the future holds a wealth of 1999, Dr Peterson was a scientist at Regeneron 22) 2002. opportunity for innovative ophthalmic drug dis- Pharmaceuticals where he conducted research on 12 More Americans Facing Blindness Than Ever Before covery and development. Within the next few retinal degeneration. Report Released On One of the years, new treatments in major unserved areas are Most-Feared Disabilities. NEI likely to emerge, such as INS365 Ophthalmic Robin S. Whitsell has six years of experience in Press Release. March 20, 2002. Solution for dry eye disease (diquafosol, Inspire) clinical development in various therapeutic areas 13 Brody B, Gamst,A,William, and Macugen for age-related macular degeneration including ophthalmology, neurology and psychia- R, Smith,A, Lau, P,Dolnak, D, Rapaport, M, Kaplan, R, Brown, (pegaptanib sodium, Eyetech). As our understand- try, cancer and pain management. She joined S. Depression, visual acuity, ing of the underlying genetics and pathophysiology Inspire Pharmaceuticals where she recently held comorbidity, and disability of ocular disease increases, more drugs will be the position of Associate Director of Clinical associated with age-related developed primarily and specifically for ophthal- Research and is now Clinical Consultant, special- macular degeneration. mology. There are already striking examples of ising in advancing research projects from drug Ophthalmology. 108 (10, p1893-900) 2001. biotech, specialty and big pharmaceutical compa- discovery through early stage clinical develop- 14 The EyeTech Study Group. nies either repositioning themselves, or entering ment. She has been with Inspire for more than Preclinical and Phase 1A clinical ophthalmology for the first time, after seeing a three years and was formerly at GlaxoWellcome evaluation of an anti-VEGF glimmer of these untapped treasures. Xalatan (now GlaxoSmithKline). She received a BA in pegylated aptamer (EYE001) for (latanoprost, Pharmacia) and Visudyne Physics and a BPh in Biophysics from Miami the treatment of exudative age- related macular degeneration. (verteporfin, Novartis/QLT) have demonstrated University in 1994. Retina. 22 (p.145-52) 2002. that as newer, better drugs enter the market, the 15 Gauthier, D, Husain, D, Kim, chance of an ophthalmic blockbuster grows. These K, Ezra, E,Tsilimbaris, M, opportunities will not only provide patients with Conolly, E, Lane,A, Gragoudas, much needed first-in-class medicines, but will also E, O’Neill, C, Miller, J. Safety and efficacy of intravitreal provide the global ophthalmic pharmaceutical injection of rhuFab VEGF in market with the potential to nearly double in size combination with verteporfin by the end of the decade. PDT on experimental choroidal . Acknowledgements IOVS. 43. (#566) 2002. 16 Slakter, J, Singerman, L, We would like to thank Dr Gary Novack and Yannuzzi, l, Russell, S, Hudson, H, Wendy Anders for their help in the preparation of Jerdan, J, Zilliox, P,Robertson, R, this article. DDW Anecortave Acetate Study Group. Sub-tenon’s Benjamin R. Yerxa, PhD has served as Vice- administration of the angiostatic agent anecortave acetate in President, Discovery for Inspire Pharmaceuticals, AMD patients with subfoveal Inc since February 2000. He joined Inspire in choroidal neovascularization August 1995 and currently supervises the (CNV) – the clinical outcome. Chemistry, Pharmacology, Preclinical and IOVS. 43. (#2909) 2002 Intellectual Property teams and all drug discovery 17 Doraiswamy, P.Non- cholinergic strategies for and early preclinical development activities. He also treating and preventing serves as the project leader for INS365 Ophthalmic Alzheimer’s disease. CNS Solution. Prior to joining Inspire he was a Research Drugs. 16 (12, p811-24) 2002

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